RESUMO
The multiple inhibition of biological targets involved in pro-inflammatory eicosanoid biosynthesis represents an innovative strategy for treating inflammatory disorders in light of higher efficacy and safety. Herein, following a multidisciplinary protocol involving virtual combinatorial screening, chemical synthesis, and in vitro and in vivo validation of the biological activities, we report the identification of 1,2,4-oxadiazole-based eicosanoid biosynthesis multi-target inhibitors. The multidisciplinary scientific approach led to the identification of three 1,2,4-oxadiazole hits (compounds 1, 2 and 5), all endowed with IC50 values in the low micromolar range, acting as 5-lipoxygenase-activating protein (FLAP) antagonists (compounds 1 and 2), and as a multi-target inhibitor (compound 5) of arachidonic acid cascade enzymes, namely cyclooxygenase-1 (COX-1), 5-lipoxygenase (5-LO) and microsomal prostaglandin E2 synthase-1 (mPGES-1). Moreover, our in vivo results demonstrate that compound 5 is able to attenuate leukocyte migration in a model of zymosan-induced peritonitis and to modulate the production of IL-1ß and TNF-α. These results are of interest for further expanding the chemical diversity around the 1,2,4-oxadiazole central core, enabling the identification of novel anti-inflammatory agents characterized by a favorable pharmacological profile and considering that moderate interference with multiple targets might have advantages in re-adjusting homeostasis.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Desenvolvimento de Medicamentos , Eicosanoides/biossíntese , Inibidores Enzimáticos/farmacologia , Oxidiazóis/farmacologia , Peritonite/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Araquidonato 5-Lipoxigenase/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 1/metabolismo , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Masculino , Camundongos , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Peritonite/induzido quimicamente , Prostaglandina-E Sintases/antagonistas & inibidores , Prostaglandina-E Sintases/metabolismo , Relação Estrutura-Atividade , ZimosanRESUMO
Harnessing the antioxidant cellular machinery has sparked considerable interest as an efficient anticancer strategy. Activating Nrf2, the master switch of the cellular redox system, suppresses ROS, alleviates oxidative stress, and halts cancer progression. 1,2,4-oxadiazoles are iconic direct Nrf2 activators that disrupt Nrf2 interaction with its endogenous repressor Keap1. This study introduces rationally designed 1,2,4-oxadiazole derivatives that inhibit other Nrf2 suppressors (TrxR1, IKKα, and NF-kB) thus enhancing Nrf2 activation for preventing oxidative stress and carcinogenesis. Preliminary screening showed that the phenolic oxadiazoles 11, 15, and 19 were comparable to ascorbic acid (ROS scavenging) and EDTA (iron chelation), and superior to doxorubicin against HepG-2, MDA-MB231, and Caco-2 cells. They suppressed ROS by 3 folds and activated Nrf2 by 2 folds in HepG-2 cells. Mechanistically, they inhibited TrxR1 (IC50; 13.19, 17.89, and 9.21 nM) and IKKα (IC50; 11.0, 15.94, and 19.58 nM), and downregulated NF-κB (7.6, 1.4 and 1.9 folds in HepG-2), respectively. They inhibited NADPH oxidase (IC50; 16.4, 21.94, and 10.71 nM, respectively) that potentiates their antioxidant activities. Docking studies predicted their important structural features. Finally, they recorded drug-like in silico physicochemical properties, ADMET, and ligand efficiency metrics.
Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Oxidiazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antioxidantes/síntese química , Antioxidantes/química , Compostos de Bifenilo/antagonistas & inibidores , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Picratos/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
Starting from isoniazid and carboxylic acids as precursors, thirteen new hydrazides and 1,3,4-oxadiazoles of 2-(4-substituted-phenoxymethyl)-benzoic acids were synthesized and characterized by appropriate means. Their biological properties were evaluated in terms of apoptosis, cell cycle blocking, and drug metabolism gene expression on HCT-8 and HT-29 cell lines. In vitro antimicrobial tests were performed by the microplate Alamar Blue assay for the anti-mycobacterial activities and an adapted agar disk diffusion technique for other non-tubercular bacterial strains. The best antibacterial activity (anti-Mycobacterium tuberculosis effects) was proved by 9. Compounds 7, 8, and 9 determined blocking of G1 phase. Compound 7 proved to be toxic, inducing apoptosis in 54% of cells after 72 h, an effect that can be predicted by the increased expression of mRNA caspases 3 and 7 after 24 h. The influence of compounds on gene expression of enzymes implicated in drug metabolism indicates that synthesized compounds could be metabolized via other pathways than NAT2, spanning adverse effects of isoniazid. Compound 9 had the best antibacterial activity, being used as a disinfectant agent. Compounds 7, 8, and 9, seemed to have antitumor potential. Further studies on the action mechanism of these compounds on the cell cycle may bring new information regarding their biological activity.
Assuntos
Anti-Infecciosos/química , Antineoplásicos/síntese química , Antituberculosos/química , Hidrazinas/síntese química , Oxidiazóis/síntese química , Anti-Infecciosos/farmacologia , Antineoplásicos/farmacologia , Antituberculosos/farmacologia , Arilamina N-Acetiltransferase/metabolismo , Benzoatos/química , Ácidos Carboxílicos/química , Avaliação Pré-Clínica de Medicamentos , Fase G1/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hidrazinas/farmacologia , Isoniazida/química , Isoniazida/farmacologia , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Oxidiazóis/química , Oxidiazóis/farmacologia , RNA Mensageiro/efeitos dos fármacosRESUMO
Direct acting antiviral drugs (DAADs) are becoming therapeutics of choice for the treatment of viral infections. Successful development of anti HIV and HCV drugs by targeting the viral proteases has provided impetus for discovering newer DAADs. Dengue virus (DENV) protease, which is composed of two nonstructural proteins, NS2B and NS3pro, can be likewise exploited for discovering new anti-dengue therapeutics. In this study, we have linked together two pharmaceutically interesting motifs, namely 1,3,4-oxadiazole and benzenesulfonamide in two alternative series to develop novel S-benzylated and S-alkylphthalimidated hybrids. For the first series of hybrids, 4-aminobenzoic acid (1) was reacted with substituted benzenesulfonyl chlorides via its amino group, whereas the carboxylic acid side was elaborated to sulfonamido-1,3,4-oxadiazole-2-thiols (6a/b) in three steps. At this stage, the intermediates 6a/b were bifurcated to either S-alkylphthalimidated (8a-j) or S-benzylated (9a-c) hybrids by reacting with corresponding halides. For the alternative series of hybrids, the carboxylic acid group of probenecid (10) was similarly elaborated to sulfonamido-1,3,4-oxadiazole-2-thiols (13), and diverged to S-alkylphthalimidated (14a-f) and S-benzylated hybrids (15a-e). Bioactivity assays demonstrated that 8g and 8h are the most potent inhibitors among the synthesized analogs, exhibiting the IC50 values of 13.9 µM and 15.1 µM, respectively. Computational assessment predicted the binding of the inhibitors at an allosteric site developed in the open conformation of DENV2 NS2B/NS3pro. Taken together these findings point out that the synthesized hybrid inhibitors possess a great potential for further antiviral drug development.
Assuntos
Vírus da Dengue/enzimologia , Oxidiazóis/química , Oxidiazóis/farmacologia , Ftalimidas/química , Ftalimidas/farmacologia , Inibidores de Proteases/farmacologia , Serina Endopeptidases/efeitos dos fármacos , Sulfonamidas/química , Sulfonamidas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Sítio Alostérico , Antivirais/farmacologia , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Simulação de Acoplamento Molecular , Oxidiazóis/síntese química , Análise Espectral/métodos , Sulfonamidas/síntese química , BenzenossulfonamidasRESUMO
Helicobacter pylori (Hp) infection is the main cause of peptic ulcer and gastric cancer. Hp eradication rates have fallen due to increasing bacterial resistance to currently used broad-spectrum antimicrobials. We have designed, synthesized, and tested redox variants of nitroethylene- and 7-nitrobenzoxadiazole-based inhibitors of the essential Hp protein flavodoxin. Derivatives of the 7-nitrobenzoxadiazole lead, carrying reduced forms of the nitro group and/or oxidized forms of a sulfur atom, display high therapeutic indexes against several reference Hp strains. These inhibitors are effective against metronidazole-, clarithromycin-, and rifampicin-resistant Hp clinical isolates. Their toxicity for mice after oral administration is low, and, when administered individually at single daily doses for 8 days in a mice model of Hp infection, they decrease significantly Hp gastric colonization rates and are able to eradicate the infection in up to 60% of the mice. These flavodoxin inhibitors constitute a novel family of Hp-specific antimicrobials that may help fight the constant increase of Hp antimicrobial-resistant strains.
Assuntos
Antibacterianos/uso terapêutico , Flavodoxina/antagonistas & inibidores , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori/efeitos dos fármacos , Oxidiazóis/uso terapêutico , Animais , Antibacterianos/síntese química , Antibacterianos/toxicidade , Desenho de Fármacos , Feminino , Células HeLa , Humanos , Camundongos Endogâmicos C57BL , Testes de Sensibilidade Microbiana , Oxidiazóis/síntese química , Oxidiazóis/toxicidadeRESUMO
Replacement of amide moiety with the 1,2,4-oxadiazole core in the scaffold of recently reported efflux pump inhibitors afforded a novel series of oxadiazole/2-imidazoline hybrids. The latter compounds exhibited promising antibacterial activity on both Gram-positive (Staphylococcus aureus, Bacillus subtilis) and Gram-negative (Escherichia coli, Pseudomonas fluorescens) strains. Furthermore, selected compounds markedly inhibited the growth of certain drug-resistant bacteria. Additionally, the study revealed the antiproliferative activity of several antibacterial frontrunners against pancreas ductal adenocarcinoma (PANC-1) cell line, as well as their type-selective monoamine oxidase (MAO) inhibitory profile.
Assuntos
Doenças Transmissíveis/tratamento farmacológico , Imidazóis/uso terapêutico , Neoplasias/tratamento farmacológico , Oxidiazóis/uso terapêutico , Antibacterianos/química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacologia , Testes de Sensibilidade Microbiana , Inibidores da Monoaminoxidase/farmacologia , Oxidiazóis/síntese química , Oxidiazóis/química , Oxidiazóis/farmacologiaRESUMO
Alzheimer's disease (AD) is a neurodegenerative disorder that has a higher prevalence and incidence in people older than 60 years. The need for improved AD therapies is unmet as the current therapies are symptomatic with modest efficacy. Partial agonists of the 5-HT4 receptor (5-HT4R) offer both symptomatic and disease-modifying treatments as they shift amyloid-precursor-protein (APP) processing from the amyloidogenic pathway to the nonamyloidogenic pathway by activating the α-secretase enzyme. In addition, they also offer symptomatic treatment by increasing levels of the neurotransmitter acetylcholine in the brain. Because of this fascinating dual mechanism of action, several chemical scaffolds having 5-HT4R pharmacophores were designed and evaluated. Most of the synthesized compounds showed potent in vitro affinities and in vivo efficacies. Upon analysis of focused structure-activity relationships, compound 4o was identified as a potent 5-HT4R partial agonist with favorable ADME properties and good in vivo efficacy. GR-125487, a selective 5-HT4R antagonist, attenuated the activity of compound 4o in the novel-object-recognition-test cognition model.
Assuntos
Amidas/química , Oxidiazóis/química , Oxidiazóis/farmacologia , Receptores 5-HT4 de Serotonina/metabolismo , Agonistas do Receptor 5-HT4 de Serotonina/química , Agonistas do Receptor 5-HT4 de Serotonina/farmacologia , Animais , Técnicas de Química Sintética , Avaliação Pré-Clínica de Medicamentos , Humanos , Masculino , Oxidiazóis/síntese química , Oxidiazóis/farmacocinética , Ratos , Ratos Wistar , Agonistas do Receptor 5-HT4 de Serotonina/farmacocinética , Relação Estrutura-AtividadeRESUMO
A lead compound A was identified previously as an stearoyl coenzyme A desaturase (SCD) inhibitor during research on potential treatments for obesity. This compound showed high SCD1 binding affinity, but a poor pharmacokinetic (PK) profile and limited chemical accessibility, making it suboptimal for use in anticancer research. To identify potent SCD1 inhibitors with more promising PK profiles, we newly designed a series of 'non-spiro' 4, 4-disubstituted piperidine derivatives based on molecular modeling studies. As a result, we discovered compound 1a, which retained moderate SCD1 binding affinity. Optimization around 1a was accelerated by analyzing Hansch-Fujita and Hammett constants to obtain 4-phenyl-4-(trifluoromethyl)piperidine derivative 1n. Fine-tuning of the azole moiety of 1n led to compound 1o (T-3764518), which retained nanomolar affinity and exhibited an excellent PK profile. Reflecting the good potency and PK profile, orally administrated compound 1o showed significant pharmacodynamic (PD) marker reduction (at 0.3mg/kg, bid) in HCT116 mouse xenograft model and tumor growth suppression (at 1mg/kg, bid) in 786-O mouse xenograft model. In conclusion, we identified a new series of SCD1 inhibitors, represented by compound 1o, which represents a promising new chemical tool suitable for the study of SCD1 biology as well as the potential development of novel anticancer therapies.
Assuntos
Antineoplásicos/química , Inibidores Enzimáticos/síntese química , Oxidiazóis/síntese química , Piridazinas/síntese química , Estearoil-CoA Dessaturase/antagonistas & inibidores , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Células HCT116 , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Microssomos Hepáticos/metabolismo , Oxidiazóis/farmacocinética , Oxidiazóis/uso terapêutico , Oxidiazóis/toxicidade , Piperidinas/química , Piperidinas/metabolismo , Piperidinas/farmacologia , Ligação Proteica , Piridazinas/farmacocinética , Piridazinas/uso terapêutico , Piridazinas/toxicidade , Compostos de Espiro/química , Estearoil-CoA Dessaturase/metabolismo , Relação Estrutura-Atividade , Transplante HeterólogoRESUMO
A series of 1, 2, 4-oxadiazole derivatives have been designed and synthesized, and 25 compounds were evaluated their abilities by the assay of cAMP concentration in GPR119-transfected HEK293T cells. All compounds showed acceptable agonistic effects on GPR119. Among these compounds, 4p exhibited the best agonistic effects with the EC50 of 20.6 nm, which was comparable to that of positive control GPR119 agonist GSK1292263. The agonistic activity of these 1,2,4-oxadiazole derivatives led to the establishment of a structure-activity relationship.
Assuntos
Hipoglicemiantes/síntese química , Oxidiazóis/química , Receptores Acoplados a Proteínas G/agonistas , AMP Cíclico/metabolismo , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Células HEK293 , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/metabolismo , Mesilatos/química , Mesilatos/metabolismo , Oxidiazóis/síntese química , Oxidiazóis/metabolismo , Ligação Proteica , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Relação Estrutura-AtividadeRESUMO
A short synthetic approach to fused 1,2,5-thiadiazoles from the corresponding 1,2,5-oxadiazoles and 1,2,5-selenadiazoles has been developed. Mono- and bis(1,2,5-thiadiazoles) were selectively obtained in high yields. The pathways for these novel reactions were discussed.
Assuntos
Oxidiazóis/química , Selênio/química , Compostos de Enxofre/química , Tiadiazóis/química , Oxidiazóis/síntese química , Oxigênio/química , Compostos de Enxofre/síntese química , Tiadiazóis/síntese químicaRESUMO
A novel series of fluconazole based mimics incorporating 1,3,4-oxadiazole moiety were designed and synthesized. All the title compounds were characterized by (1)H-NMR, (13)C-NMR, and Q-TOF-MS. Preliminary results revealed that most of analogues exhibited significant antifungal activity against seven pathogenic fungi. Compounds 9g and 9k (MIC80 ≤ 0.125 µg/mL, respectively) were found more potent than the positive controls itraconazole and fluconazole as broad-spectrum antifungal agents. The observed docking results showed that the 1,3,4-oxadiazole moiety enhanced the affinity binding to the cytochrome P450 14α-demethylase (CYP51).
Assuntos
Antifúngicos/síntese química , Fluconazol/análogos & derivados , Fluconazol/síntese química , Oxidiazóis/síntese química , Antifúngicos/farmacologia , Sítios de Ligação , Candida albicans/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Fluconazol/farmacologia , Humanos , Testes de Sensibilidade Microbiana/métodos , Oxidiazóis/farmacologia , Relação Estrutura-AtividadeRESUMO
Developing new antiretroviral therapies for HIV-1 infection with potential for less frequent dosing represents an important goal within drug discovery. Herein, we present the discovery of ethylâ (1-((4-((4-fluorobenzyl)carbamoyl)-1-methyl-2-(2-(5-methyl- 1,3,4-oxadiazole-2-carboxamido)propan-2-yl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)ethyl) carbonate (MK-8970), a highly optimized prodrug of raltegravir (Isentress). Raltegravir is a small molecule HIV integrase strand-transfer inhibitor approved for the treatment of HIV infection with twice-daily administration. Two classes of prodrugs were designed to have enhanced colonic absorption, and derivatives were evaluated in pharmacokinetic studies, both in vitro and in vivo in different species, ultimately leading to the identification of MK-8970 as a suitable candidate for development as an HIV therapeutic with the potential to require less frequent administration while maintaining the favorable efficacy, tolerability, and minimal drug-drug interaction profile of raltegravir.
Assuntos
Inibidores de Integrase de HIV/química , Oxidiazóis/química , Pró-Fármacos/química , Pirimidinonas/química , Pirrolidinonas/química , Acetais/química , Animais , Área Sob a Curva , Carbonatos/química , Cães , Avaliação Pré-Clínica de Medicamentos , Integrase de HIV/química , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/farmacocinética , HIV-1/enzimologia , Meia-Vida , Hepatócitos/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Masculino , Oxidiazóis/síntese química , Oxidiazóis/farmacocinética , Pró-Fármacos/síntese química , Pró-Fármacos/farmacocinética , Pirimidinonas/síntese química , Pirimidinonas/farmacocinética , Curva ROC , Raltegravir Potássico , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
Phidianidines (1), isolated from the marine opisthobranch mollusk Phidiana militaris, present the first example of natural products possessing an 1,2,4-oxadiazole ring system and show various bioactivities. However, the structure-activity relationship study related to 1 has not been reported yet. As our ongoing effect toward marine-derived potential neuroprotective agents, a series of phidianidine-based derivatives have been synthesized and evaluated for neuroprotective effects against amyloid-ß25-35 (Aß25-35)-, hydrogenperoxide (H2O2)-, and oxygen-glucose deprivation (OGD)-induced neurotoxicity in SH-SY5Y cells. The bioassay results indicated that some of analogs, especially 2q and 2r, exhibited good in vitro neuroprotective effects in the above three screening models. The preliminary SAR study indicated that substituent groups introduced to the benzene ring play a crucial role in their bioactivity. In particular, the linear alkoxy group at 4-position favors the neuroprotective activity, while a bulky group could lead the activity decrease or loss. These findings could provide an alternative strategy for the development of novel indole-based 1,2,4-oxadiazole derivatives for the treatment of Alzheimer's disease.
Assuntos
Indóis/síntese química , Fármacos Neuroprotetores/síntese química , Oxidiazóis/síntese química , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Indóis/farmacologia , Moluscos , Fármacos Neuroprotetores/farmacologia , Oxidiazóis/farmacologiaRESUMO
The treatment of neurodegenerative diseases is difficult because of multiple etiologies and the interplay of genetics and environment as precipitating factors. In the case of amyotrophic lateral sclerosis (ALS), we have knowledge of a handful of genes that cause disease when mutated. However, drugs to counteract the effect of genetic mutations have not yet been found. One of the causative genes, Cu, Zn-superoxide dismutase (SOD1) is responsible for about 10-15% of the genetically linked autosomal dominant disease. Our rationale was that compounds that reduce expression of the mutant protein would be beneficial to slow onset and/or disease progression. We screened candidate compounds using a cell-based in vitro assay for those that reduce mutant SOD1 (G93A) protein expression. This led to the discovery of 2-[3-iodophenyl)methylsulfanyl]-5pyridin-4-yl-1,3,4-oxadiazole, a known protein kinase inhibitor that decreases G93A-SOD1 expression in vitro and in the brain and spinal cord in vivo. However, this compound has a biphasic dose response curve and a likely toxophore which limit its therapeutic window for chronic disease such as ALS. Therefore, we designed and tested a focused library of analogs for their ability to decrease SOD1 expression in vitro. This exercise resulted in the identification of a lead compound with improved drug-like characteristics and activity. Development of small molecules that reduce the expression of etiologically relevant toxic proteins is a strategy that may also be extended to familial ALS linked to gain of function mutations in other genes.
Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Oxidiazóis/química , Oxidiazóis/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Superóxido Dismutase/metabolismo , Animais , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Camundongos , Oxidiazóis/síntese química , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Superóxido Dismutase/antagonistas & inibidoresRESUMO
A novel series of pyrazoline amidoxime (2a-d) and pyrazoly-1,2,4-oxadiazole (3a-p) and (4) of pharmacological significance have been synthesised. Structures of newly synthesised compounds were characterized by spectral studies. New compounds were screened for their in vitro antioxidant, antimicrobial and antiinflammatory activities. Among the synthesized compounds, compound 2a, 3l and 3o were found to be active antimicrobial agents in addition to having potent antioxidant activity, while the compound 3f showed promising antiinflammatory activity in comparison with standard drug.
Assuntos
Bactérias/efeitos dos fármacos , Fungos/efeitos dos fármacos , Oxidiazóis/síntese química , Oxidiazóis/farmacologia , Oximas/síntese química , Oximas/farmacologia , Amidas/síntese química , Amidas/química , Amidas/farmacologia , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antioxidantes/síntese química , Antioxidantes/química , Antioxidantes/farmacologia , Bioensaio , Avaliação Pré-Clínica de Medicamentos , Ácidos Graxos/síntese química , Ácidos Graxos/química , Ácidos Graxos/farmacologia , Estrutura Molecular , Oxidiazóis/química , Oximas/química , Pirazóis/síntese química , Pirazóis/química , Pirazóis/farmacologiaRESUMO
Helicobacter pylori (Hp) infection affects one-half of the human population and produces a variety of diseases from peptic ulcer to cancer. Current eradication therapies achieve modest success rates (around 70%), resistance to the antibiotics of choice is on the rise, and vaccination has not proved to be successful yet. Using an essential Hp protein, flavodoxin, as target, we identified three low-molecular-weight flavodoxin inhibitors with bactericidal anti-Hp properties. To improve their therapeutic indexes, we have now identified and tested 123 related compounds. We have first tested similar compounds available. Then we have designed, synthesized, and tested novel variants for affinity to flavodoxin, MIC for Hp, cytotoxicity, and bactericidal effect. Some are novel bactericidal inhibitors with therapeutic indexes of 9, 38 and 12, significantly higher than those of their corresponding leads. Developing novel Hp-specific antibiotics will help fighting Hp resistance and may have the advantage of not generally perturbing the bacterial flora.
Assuntos
Antibacterianos/síntese química , Flavodoxina/antagonistas & inibidores , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori/efeitos dos fármacos , Antibacterianos/química , Antibacterianos/farmacologia , Benzopiranos/síntese química , Benzopiranos/química , Benzopiranos/farmacologia , Células HeLa , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Oxidiazóis/síntese química , Oxidiazóis/química , Oxidiazóis/farmacologia , Ligação Proteica , Relação Estrutura-Atividade , Estirenos/síntese química , Estirenos/química , Estirenos/farmacologiaRESUMO
A series of 5-(alkyl(1H-indol-3-yl))-2-(substituted)-1,3,4-oxadiazoles were efficiently synthesized by oxidative cyclisation of N'-benzylidene-(1H-indol-3-yl)alkane hydrazides using di(acetoxy)iodobenzene. N'-Benzylidene-(1H-indol-3-yl)alkane hydrazides themselves were derived from simple indole-3-carboxylic acids. The 5-(alkyl(1H-indol-3-yl))-2-(substituted)-1,3,4-oxadiazoles were evaluated for their anti-inflammatory and anti-proliferative activities. Based on the results obtained structure and activity relationship (SAR) was established and a correlation between the activities was observed. Compound 6i and 6t showed best activity against proliferation of human cancer cell lines and as well as inflammation of rat paw edema.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacologia , Oxidiazóis/síntese química , Oxidiazóis/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Avaliação Pré-Clínica de Medicamentos , Humanos , Masculino , Oxidiazóis/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Given its role in the mediation of energy and glucose homeostasis, the G-protein-coupled bile acid receptorâ 1 (TGR5) is considered a potential target for the treatment of typeâ 2 diabetes mellitus and other metabolic disorders. By thorough analysis of diverse structures of published TGR5 agonists, a hypothetical ligand-based pharmacophore model was built, and a new class of potent TGR5 agonists, based on the novel 3,4,5-trisubstituted 4,5-dihydro-1,2,4-oxadiazole core, was discovered by rational design. Three distinct synthetic methods for constructing 4,5-dihydro-1,2,4-oxadiazoles and extensive structure-activity relationship studies are reported herein. Compound (R)-54 n, the structure of which was determined by single-crystal X-ray diffraction and quantum chemical solid-state TDDFT-ECD calculations, showed the best potency, with an EC50 value of 1.4â nM toward hTGR5. Its favorable properties inâ vitro warrant further investigation.
Assuntos
Desenho de Fármacos , Oxidiazóis/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Células HEK293 , Humanos , Modelos Moleculares , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Teoria Quântica , Relação Estrutura-AtividadeRESUMO
A series of 1,3,4-oxadiazole derivatives containing 1,4-benzodioxan moiety (7a-7q) have been designed, synthesized and evaluated for their antitumor activity. Most of the synthesized compounds were proved to have potent antitumor activity and low toxicity. Among them, compound 7a showed the most potent biological activity against Human Umbilical Vein Endothelial cells, which was comparable to the positive control. The results of apoptosis and flow cytometry (FCM) demonstrated that compound 7a induce cell apoptosis by the inhibition of MetAP2 pathway. Molecular docking was performed to position compound 7a into MetAP2 binding site in order to explore the potential target.
Assuntos
Aminopeptidases/antagonistas & inibidores , Antineoplásicos/farmacologia , Dioxanos/química , Inibidores Enzimáticos/farmacologia , Glicoproteínas/antagonistas & inibidores , Oxidiazóis/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Aminopeptidases/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Glicoproteínas/metabolismo , Células Endoteliais da Veia Umbilical Humana/enzimologia , Humanos , Metionil Aminopeptidases , Modelos Moleculares , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Inibidores de Proteases/química , Inibidores de Proteases/classificação , Relação Estrutura-AtividadeRESUMO
AZD9272 and AZD6538 are two novel mGluR5 negative allosteric modulators selected for further clinical development. An initial high-throughput screening revealed leads with promising profiles, which were further optimized by minor, yet indispensable, structural modifications to bring forth these drug candidates. Advantageously, both compounds may be synthesized in as little as one step. Both are highly potent and selective for the human as well as the rat mGluR5 where they interact at the same binding site than MPEP. They are orally available, allow for long interval administration due to a high metabolic stability and long half-lives in rats and permeate the blood brain barrier to a high extent. AZD9272 has progressed into phase I clinical studies.